Medicament delivery formulations, devices and methods

ABSTRACT

Disclosed are medicinal compositions, and devices, methods and systems which use same, comprising a propellant and at lease one medicinally active compound, said propellant comprising at least one fluoroolefin having at least two but less than seven carbon atoms.

RELATED APPLICATIONS

The present application is a division of U.S. application Ser. No.11/376,826, filed Mar. 15, 2006 which application is related to andclaims the priority benefit of U.S. Patent Application Ser. No.60/662,579. The present application is also a divisional of U.S. patentapplication Ser. No. 10/837,521 filed Apr. 29, 2004 (now U.S. Pat. No.7,655,610, issued Feb. 2, 2010), entitled “Heat Transfer FluidComprising Trans-1,3,3,3-tetrafluoropropene,” and a divisional of U.S.patent application Ser. No. 10/837,526 filed Apr. 29, 2004 (now U.S.Pat. No. 7,524,805, issued Apr. 28, 2009), entitled “Azeotrope-likeCompositions of Tetrafluoropropene and Carbon Dioxide. The presentapplication is also a continuation-in-part of U.S. patent applicationSer. No. 10/837,525, filed Apr. 29, 2004 (now U.S. Pat. No. 7,279,451,issued Oct. 9, 2007).

FIELD OF THE INVENTION

This invention relates to medicament delivery compositions, systems,devices and methods. In particular aspects, this invention relates tomedicinal aerosol formulations, methods and devices, such as those usedin connection with pulmonary, nasal, buccal or topical administration ofmedicaments.

BACKGROUND OF THE INVENTION

Metered dose inhalers (MDIs) have long been used to deliver medicaments,such as bronchodilator drugs and steroids, to the areas of patientsneeding treatment. Compared with oral administration of bronchodilators,inhalation therapy using MDIs frequently has the advantage of relativelyrapid onset of action and relatively low instance of systemic sideeffects.

In general, MDIs are dependent upon the propulsive force of a propellantto help transport the medicament to the area or areas needing treatment,which sometimes are referred to herein as the “target area.” Thepropellant has heretofore generally comprised a mixture of liquefiedchlorofluorocarbons (CFC's) selected to have the vapor pressurenecessary to produce the desired propulsive force while at the same timeproviding stability of the medicament formulation. Methane and ethaneseries CFCs, such tetrachloromethane (CFC-11), trichlorofluoromethane(CFC-12) and 1,2 dichlorotetrafluoroethane (CFC-114), have commonly beenused as propellants in aerosol formulations for inhalationadministration.

The use of CFCs has environmental drawbacks. It is now known that CFC'stend to react with the ozone layer around the earth and thereby resultin some level of ozone depletion. As a result various governmental andinternational organizations have been engaged in efforts to reduce oreliminate the use of CFCs. The volume of CFCs which have been used inconnection with MDIs may be considered low compared to other uses, suchas refrigerants and blowing agents. Nevertheless, a potential ozonedepletion advantage may be achieved by reducing or eliminating CFCs fromMDIs and other medicament delivery systems.

Because of the potential damage to the earth's ozone layer caused bychlorine-containing compounds (such as chlorofluorocarbons (CFCs),hydrochlorofluorocarbons (HCFCs) and the like), there has thus been anincreasing need for new fluorocarbon and hydrofluorocarbon compounds andcompositions that offer alternatives with reduced ozone depletionpotential. For example, efforts are under way to replacechlorine-containing propellants with non-chlorine-containing compoundsthat will not deplete the ozone layer, such as hydrofluorocarbons(HFCs).

U.S. Pat. No. 5,776,434—Purewal, et al. has recognized the ozonedepletion problem of CFCs and has proposed the use of a non-chlorinecontaining compound, namely, 1,1,1,2-tetrafluoroethane (sometimesreferred to herein as HFA-134a or HFC-134a) as a propellant formedicinal aerosol formulations when used in combination with a surfaceactive agent and an adjuvant having a higher polarity than1,1,1,2-tetrafluoroethane. However, in 1998 the International Programmeon Chemical Safety (IPCS), published a Concise International ChemicalAssessment Document (No. 11) indicating that 1,1,1,2-tetrafluoroethanehas a significant global warming potential.

HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane) has also been proposed aslow ozone depletion potential substitute for CFCs in MDIs. However, thiscompound also has a significant global warming potential.

U.S. Pat. No. 6,111,150 describes chlorofluor- and fluoro-substitutedpropenes as being “useful as an intermediate of medicines . . . ”(col.2, l. 4). However, there is no disclosure or suggestion of MDIs orany of the propellant materials used in MDIs. U.S. Pat. Nos. 3,723,318and 3,884,826 each describes the use of trifluoropropene in connectionwith aerosol propellants and refrigerants, but there is no disclosure orsuggestion in these patents relating to MDIs, nor is there anydisclosure or suggestion regarding the use of tetrafluoropropene as anaerosol or in connection with MDIs.

Bromine-containing halocarbon additives have been suggested for use inconnection with efforts to reduce the flammability of numerousmaterials, including aerosol propellants, in U.S. Pat. No.5,900,185—Tapscott. The additives described in this patent are said tobe characterized by high efficiency and short atmospheric lifetimes,that is, low ozone depletion potential (ODP) and a low global warmingpotential (GWP). The patent discloses the use of such compounds inamounts of from about 0.1 to about 20 percent by weight.

While the brominated olefins described in Topscott may have some levelof effectiveness in connection with use as anti-flammability agents inconnection with certain materials, there is no disclosure of the use ofsuch materials as an aerosol or propellant. Furthermore, it is believedthat such compounds may also have certain disadvantages. For example,applicants have come to recognize that many of the compounds identifiedin Topscott will have a relatively low efficiency as a blowing agent dueto the relatively high molecular weight of such compounds. In addition,it is believed that many of the compounds disclosed in Tapscott willencounter problems when used as a blowing agent due to the relativelyhigh boiling point of such compounds. Moreover, it is understood byapplicants that many compounds which have a high level of no meanssubstitution may possess undesirable toxicity properties and/or otherundesirable properties, such as potentially environmentally undesirablebioaccumulation.

Thus, applicants have recognized a need for compounds, compositions,systems, devices and methods for medicament delivery that at onceprovide relatively low ozone depletion potential and relatively lowglobal warming potential. Moreover, applicants have recognized that anycomposition, including any propellant contained therein, must alsopossess properties which ensure the efficacy of the medicament, such asmedicament stability, low- or no-toxicity, and compatibility with theother components of the medicament delivery system.

SUMMARY

Applicants have found that many of the shortcomings of the priorcompositions can be overcome and/or that many of the above-noted needscan be satisfied by medicinal compositions, and by devices, methods andsystems which use same, comprising a propellant and at least onemedicinally active compound, said propellant comprising at least onefluoroolefin, preferably hydrofluoroolefin, which is a medicinallyacceptable carrier for said medicinally active compound and having atleast two but less than seven, preferably less than six, and even morepreferably less than five carbon atoms. As used herein, the termmedicinally acceptable carrier refers to materials which are at leastnot substantially harmful to the intended recipient of the medicinallyactive compound. As used herein, the term fluoroolefin means an organiccompound comprising at least carbon and fluorine and at least onecarbon-carbon double bond, with other substituents being optionallypresent. As used herein, the term hydrofluoroolefin means an organiccompound comprising carbon, hydrogen and fluorine and at least onecarbon-carbon double bond, with other substituents being optionallypresent, although in certain preferred embodiments chlorine is notpresent. As used herein, the terms “medicinal,” “medicament,” and thelike are used in their ordinary broad sense to refer to any and allmaterials or substances which have, or at least are believed to have,the property of healing, treating or relieving disease, injury or otherailment, and/or the pain or other symptoms of same, and/or of diagnosingsame, such would include for example drugs and biologically activesubstances. Thus, the term “medicinally active compound,” is used hereinto refer to a compound or combinations of compounds which are effective,or at least are believed to be effective, in a medicinal sense.

In certain preferred embodiments, the fluoroolefin of the presentinvention comprises, preferably comprises in major proportion, and evenmore preferably consists essentially of, one or more compounds ofFormula I as follows:

XCF_(z)R_(3-z)  (I)

where X is a C₂ or a C₃ unsaturated, substituted or unsubstituted, alkylradical, each R is independently F, Br, I, Cl or H, and z is 1 to 3, butwhere it is generally not preferred for R to be Cl. In preferredembodiments, the Formula I compound is tetrafluoropropene, morepreferably 1,1,1,3-tetrafluoropropene (HFO-1234ze) and/or1,1,1,2-tetrafluoropropene (HFO-1234yf). The term HFO-1234ze is usedherein generically to refer to 1,1,1,3-tetrafluoropropene, independentof whether it is the cis- or trans-form. The terms “cisHFO-1234ze” and“transHFO-1234ze” are used herein to describe the cis- and trans-formsof 1,1,1,3-tetrafluoropropene respectively. The term “HFO-1234ze”therefore includes within its scope cisHFO-1234ze, transHFO-1234ze, andall combinations and mixtures of these. In certain preferredembodiments, the composition comprises, the trans-isomer of1,1,1,3-tetrafluoropropene.

In certain of the preferred composition of the present invention thepropellant does not have a substantial negative effect on atmosphericchemistry. More specifically, in the preferred compositions thepropellant of the present invention has a very low or negligiblecontribution to ozone depletion in comparison to some of the heretoforecommonly used halogenated species. The preferred compositions thus havethe advantage of not contributing substantially to ozone depletion. Thepreferred compositions also do not contribute substantially to globalwarming compared to many of the hydrofluoroalkanes which have beencommonly used.

BRIEF DESCRIPTION OF THE DRAWING

The invention will now be described with reference to the accompanyingdrawings in which:

FIG. 1 represents a cross-section through an inhaler in accordance withone embodiment of the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

I. The Compositions

It is contemplated that the compositions of the present invention can beused in a wide variety of forms, and all such forms are within the broadscope of the present invention. In general, it is preferred that presentcompositions are in a form suitable for delivery to the particular siteon or in the human or other mammal needing treatment, or to a site whichis the preferred location for introduction into the body, even if thetreatment or diagnosis is required at other areas. For example, thepreferred compositions of the present invention are generally welladapted for delivery through the mouth, nose, ears and/or other mucosalmembranes, or by transdermal application. It is possible, therefore,that the compositions of the present invention may be delivered to thelungs for treatment of a malady occurring in the lungs or as a mechanismfor introducing the medicament into the system (e.g., bloodstream) ofthe user in order to treat a malady elsewhere.

The amount of medicinal compound(s) present relative to the amount ofpropellant can vary widely in accordance with the present invention, andall such proportions are believed to be adaptable for use within thescope hereof, provided of course that the total amount of medicinallyactive agent is therapeutically effective, or at least believed to betherapeutically effective by the doctor or other professionalprescribing the medicament. In certain preferred embodiments, however,the present compositions comprise at least about 50% by weight, and evenmore preferably from about 60% to about 99%, or more, by weight, ofpropellant based upon the total weight of the composition. Furthermore,it is preferred in certain embodiments that the composition comprisefrom about 0.01% to about 0.5% by weight of medicinally activecompounds, although it is appreciated that lesser or greater amounts maybe used depending upon the particular medicament, the prescribed dosageand other numerous factors.

A. The Medicinally Active Compound

Although it is contemplated that the medicinally active compounds of theinvention may be present in a wide variety of forms, it is preferred inmany embodiments that the medicinally active agent or compound is partof a solution, dispersion, suspension, emulsion, or the like. Asexplained in more detail hereinafter, the medicinal compounds of thepresent invention are frequently present as particles having varioussizes and other physical properties, although fine particulate form isgenerally preferred for the formation of stable, substantially uniformdispersions, suspensions, etc. of the medicinal compounds. It will beappreciated, in addition, that in certain embodiments two or moremedicinally active substances are included in the present compositions,and in yet further embodiments, at least one of said medicinally activesubstances is present in a dissolved form in a liquid phase and/or atleast one other of said medicinally active substances is present insuspended form in a fluid, preferably a liquid phase.

In certain embodiments, the medicinal compounds of the present inventionare preferably used in micronized or micro-particulate form. Such formspreferably exhibit a relatively hollow and porous morphology, and alsopreferably have a mass average aerodynamic diameter (MAAD) of notgreater than about 10 microns, but preferably less than about 5 microns.Medicinal compounds of this type are preferred for use in many MDIapplications. The use of such micro-particulate medicinal compounds incombination with the propellant components of the present invention isbelieved to produce especially stable and effective compositions.

One problem associated with many medicinal compositions, particularlythose adapted for use in connection with MDIs, is the tendency of theindividual particles of the medicinally active compound to agglomerate.As described in detail hereinafter, certain embodiments of the presentinvention include one or more adjuvants to stabilize the compositionagainst this and other types of undesirable change. In addition, certainembodiments hereof enhance the stability of the composition by usingand/or altering particle morphology to reduce attractive forces betweenthe dispersed components and to reduce density differences, therebyretarding degradation of the suspensions, dispersions, etc. byflocculation, sedimentation or creaming. Such enhancements in certainembodiments may facilitate uniform dose delivery by MDIs, and allow formore concentrated dispersions. In such preferred embodiments, at least asubstantial proportion of the medicinally active particles, andpreferably a major proportion, have hollow and/or porous perforatedmicrostructures that substantially reduce attractive forces, such as vander Waals forces. Without being bound by or to any particular theory ofoperation, the use of perforated (or porous) microstructures ormicroparticulates that are permeated or filled by the surrounding fluidor suspension medium (which generally includes the propellant of thepresent invention), is believed to significantly reduce disruptiveattractive forces between the particles. Moreover, the components of thedispersions may be selected to minimize differences in polarizabilities(i.e. reduced Hamaker constant differentials) and further stabilize thepreparation. In certain preferred embodiments, the dispersions of thepresent invention are substantially homogeneous with only minordifferences in density between particles, preferably as defined by theperforated microparticulates and the suspension medium. Such perforatedmicroparticles are disclosed in U.S. Pat. No. 6,638,495, which isincorporated herein by reference.

With respect to the particular type of medicinal compound or agent,those skilled in the art will appreciate that any therapeutic ordiagnostic agent may be incorporated into the present composition,preferably the dispersions of the present invention. For example, themedicinal compound may be selected from the group consisting ofantiallergics, bronchodilators, bronchoconstrictors, pulmonary lungsurfactants, analgesics, antibiotics, leukotriene inhibitors orantagonists, anticholinergics, mast cell inhibitors, antihistamines,antiinflammatories, antineoplastics, anesthetics, anti-tuberculars,imaging agents, cardiovascular agents, enzymes, steroids,corticosteroids, short acting beta-agonists, long-acting beta-agonists,genetic material, viral vectors, antisense agents, proteins, peptides,anti-asthma medication and combinations of any two or more thereof.Particularly preferred medicinal agents for use in accordance with theinvention include anti-allergics, peptides and proteins, bronchodilatorsand anti-inflammatory steroids for use in the treatment of respiratorydisorders, such as asthma and chronic obstructive pulmonary disorder(COPD), by inhalation therapy.

Exemplary medicaments or bioactive agents may be selected from, forexample, analgesics, e.g. codeine, dihydromorphine, ergotamine,fentanyl, or morphine; anginal preparations, e.g. diltiazem; mast cellinhibitors, e.g. cromolyn sodium; antiinfectives, e.g. cephalosporins,macrolides, quinolines, penicillins, streptomycin, sulphonamides,tetracyclines and pentamidine; antihistamines, e.g. methapyrilene;anti-inflammatories, e.g. fluticasone propionate, beclomethasonedipropionate, flunisolide, budesonide, mometasone furoate, tripedane,cortisone, prednisone, prednisilone, dexamethasone, betamethasone, ortriamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators,e.g. ephedrine, epinephrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, salbutamol (albuterol), salmeterolxinafoate, terbutaline; diuretics, e.g. amiloride; anticholinergics,e.g. ipratropium bromide, tiotropium, atropine, or oxitropium; lungsurfactants e.g. Surfaxin, Exosurf, Survanta; xanthines, e.g.aminophylline, theophylline, caffeine; therapeutic proteins andpeptides, e.g. DNAse, insulin, glucagon, LHRH, nafarelin, goserelin,leuprolide, interferon, rhu IL-1 receptor, macrophage activation factorssuch as lymphokines and muramyl dipeptides, opioid peptides andneuropeptides such as enkaphalins, endorphins, renin inhibitors,cholecystokinins, DNAse, growth hormones, leukotriene inhibitors and thelike. In addition, bioactive agents that comprise an RNA or DNAsequence, particularly those useful for gene therapy, geneticvaccination, genetic tolerization, or antisense applications, may beincorporated in the disclosed dispersions as described herein.Representative DNA plasmids include pCMV.beta. (available from GenzymeCorp, Framington, Mass.) and pCMV-.beta.-gal (a CMV promotor linked tothe E. coli Lac-Z gene, which codes for the enzyme.beta.-galactosidase), and any combination of two or more of these. Inmany prefer embodiments, at least two different medicinally activecompounds in combination, are included in the composition.

B. The Propellant

In preferred embodiments, one of the primary functions of the propellantof the present invention is to provide a source of kinetic energy to aidin delivery of the medicinal compounds to the desired site. MDIs, forexample, generally depend upon the propulsive force of the propellantsystem used in its manufacture. The propellant system preferably notonly provides the desired vapor pressure to, but it also at least doesnot degrade, and preferably enhances the stability of the suspension. Itis contemplated that the present propellant systems may be used todeliver solubilized or suspended agents and/or, in preferredembodiments, to deliver selected medicinal compound in fine particulateform to provide a dispersion. Thus, in certain preferred embodiments ofthe present invention the propellant also serves to carry and/orsolubilize and/or suspend one or more of the medicinal compounds of thepresent invention.

With respect to the preferred compound(s) for use in the presentinvention, the propellant comprises, preferably consists essentially of,and in some preferred embodiments consists of, at least onefluoroolefin, preferably a hydrofluoroolefin containing from 3 to 4carbon atoms, preferably three carbon atoms. The hydrofluoroolefincompounds of the present invention are sometimes referred to herein forthe purpose of convenience as “HFOs” if they contain at least onehydrogen, at least one fluorine and no chlorine. Although it iscontemplated that certain HFOs of the present invention may contain twocarbon-carbon double bonds, such compounds at the present time are notconsidered to be preferred.

As mentioned above, the present compositions preferably comprise one ormore compounds in accordance with Formula I. In preferred embodiments,the compositions include compounds of Formula II below:

where each R is independently F, Br, I, Cl or H, but preferably not Cl

R′ is (CR₂)_(n)Y,

Y is CRF₂

and n is 0 or 1.

In highly preferred embodiments, Y is CF₃, n is 0 and at least one ofthe remaining Rs is F.

Applicants believe that, in general, the compounds of the aboveidentified Formulas I and II are generally effective as propellants inmedicinal compounds as described herein, particularly in connection withaerosol compositions. However, applicants have surprisingly andunexpectedly found that certain forms of the compounds having astructure in accordance with the formulas described above exhibit ahighly desirable low level of toxicity compared to other of suchcompounds. As can be readily appreciated, this discovery is ofpotentially enormous and critical importance to the formulation ofmedicinal compositions, since pharmacologically and medicinallyacceptable excipients should generally not have a substantially level oftoxicity. More particularly, applicants believe that relatively lowtoxicity levels are associated with compounds of Formula II, preferablywherein Y is CF₃, wherein at least one R on the unsaturated terminalcarbon is H, and at least one of the remaining Rs is F. Applicantsbelieve also that all structural, geometric and stereoisomers of suchcompounds are effective and of beneficially low toxicity.

In highly preferred embodiments, especially embodiments comprising thelow toxicity compounds described above, n is zero. In certain highlypreferred embodiments the compositions of the present inventioncomprise, and in certain embodiments consists essentially of, one ormore tetrafluoropropenes. As mentioned above, the term “HFO-1234” isused herein to refer to all tetrafluoropropenes. Among thetetrafluoropropenes, HFO-1234yf is particularly preferred in manyembodiments. HFO-1234ze, in the cis- and/or trans-forms are may bepreferred also in certain embodiments. As also mentioned above, the termHFO-1234ze is used herein generically to refer to1,1,1,3-tetrafluoropropene, independent of whether it is the cis- ortrans-form, and the terms “cisHFO-1234ze” and “transHFO-1234ze” are usedherein to describe the cis- and trans-forms of1,1,1,3-tetrafluoropropene respectively. In certain preferredembodiments, the HFO-1234ze comprises a combination of transHFO-1234zeand cisHFO-1234ze, and more preferably from about 90% to about 99% transon the basis of total HFO-1234ze, with the cis isomer comprising fromabout 1% to about 10% of the same basis. The propellant compositions ofthe present invention therefore comprise in certain embodiments acombination of cisHFO-1234ze and transHFO1234ze, preferably in acis:trans weight ratio of from about 1:99 to about 10:99, morepreferably from about 1:99 to about 5:95, and even more preferably fromabout 1:99 to about 3:97.

Although the properties of cisHFO-1234ze and transHFO-1234ze differ inat least some respects, it is contemplated that each of these compoundsis adaptable for use, either alone or together with other compoundsincluding its stereoisomer, in connection with each of the applications,methods, systems and devices described herein. For example, whiletransHFO-1234ze may be preferred for use in certain systems because ofits relatively low boiling point (−19° C.), it is neverthelesscontemplated that cisHFO-1234ze, with a boiling point of +9° C., alsohas utility in connection with the present invention. Accordingly, it isto be understood that the terms “HFO-1234ze” and1,1,1,3-tetrafluoropropene refer to both stereo isomers, and the use ofthis term is intended to indicate that each of the cis- and trans-formsapplies and/or is useful for the stated purpose unless otherwiseindicated.

HFO-1234 compounds are known materials and are listed in ChemicalAbstracts databases. The production of fluoropropenes such as CF₃CH═CH₂by catalytic vapor phase fluorination of various saturated andunsaturated halogen-containing C₃ compounds is described in U.S. Pat.Nos. 2,889,379; 4,798,818 and 4,465,786, each of which is incorporatedherein by reference. EP 974,571, also incorporated herein by reference,discloses the preparation of 1,1,1,3-tetrafluoropropene by contacting1,1,1,3,3-pentafluoropropane (HFC-245fa) in the vapor phase with achromium-based catalyst at elevated temperature, or in the liquid phasewith an alcoholic solution of KOH, NaOH, Ca(OH)₂ or Mg(OH)₂. Inaddition, methods for producing compounds in accordance with the presentinvention are described generally in connection with pending UnitedStates patent application entitled “Process for ProducingFluoropropenes” bearing U.S. application Ser. No. 13/226,019, now U.S.Pat. No. 8,247,624, which is also incorporated herein by reference.

The present compositions, particularly those comprising HFO-1234(including HFO-1234yf and HFO-1234ze), are believed to possessproperties that are advantageous for a number of important reasons. Forexample, applicants believe, based at least in part on mathematicalmodeling, that the fluoroolefins of the present invention will not havea substantial negative affect on atmospheric chemistry, being negligiblecontributors to ozone depletion in comparison to some other halogenatedspecies. The preferred compositions of the present invention thus havethe advantage of not contributing substantially to ozone depletion. Thepreferred compositions also do not contribute substantially to globalwarming compared to many of the halogenated molecules presently in use.

In certain preferred forms, compositions of the present invention have aGlobal Warming Potential (GWP) of not greater than about 1000, morepreferably not greater than about 500, and even more preferably notgreater than about 150. In certain embodiments, the GWP of the presentcompositions is not greater than about 100 and even more preferably notgreater than about 75. As used herein, “GWP” is measured relative tothat of carbon dioxide and over a 100-year time horizon, as defined in“The Scientific Assessment of Ozone Depletion, 2002, a report of theWorld Meteorological Association's Global Ozone Research and MonitoringProject,” which is incorporated herein by reference.

In certain preferred forms, the present compositions also preferablyhave an Ozone Depletion Potential (ODP) of not greater than 0.05, morepreferably not greater than 0.02 and even more preferably about zero. Asused herein, “ODP” is as defined in “The Scientific Assessment of OzoneDepletion, 2002, A report of the World Meteorological Association'sGlobal Ozone Research and Monitoring Project,” which is incorporatedherein by reference.

The amount of the fluoroolefins, particularly the Formula I compounds,and even more particularly HFO-1234, contained in the propellantcomponent of present compositions can vary widely, depending uponnumerous factors relevant to each particular use of the composition, andpropellants comprising more than trace amounts and up to and including100% of the compound are within the broad scope of the presentinvention. Moreover, the compositions of the present invention can beazeotropic, azeotrope-like or non-azeotropic. In preferred embodiments,the present compositions comprise HFO-1234, preferably HFO-1234ze, inamounts from about 5% by weight to about 99% by weight, and even morepreferably from about 5% to about 95%_(.)

Many compounds that are not fluoroolefins, and particularly not inaccordance with Formula (I), may be combined with the such compound(s)of the present invention to form the propellant, and the presence of allsuch compounds is within the broad scope of the invention. In certainpreferred embodiments, the present compositions include, in addition tothe fluoroolefin compound(s), preferably of Formula (I) and even morepreferably HFO-1234ze, one or more other hydrofluoralkenes, as well ashydrofluoroalkanes, fluorocarbons, perfluorocarbons,fluorocarbon/hydrocarbon diblocks, hydrocarbons, alcohols and ethers.

In certain preferred embodiments, the propellant of the presentinvention comprises one or more compound(s) of Formula (I), preferablyin an amount of about 1 percent by weight to about 99 percent by weightbased on the weight of the total propellant, and one or morehydrofluorocarbons (HFCs), such as, for example hydrofluoroethanes (eg.,pentafluoroethane (HFC-125), 1,1,2,2-tetrafluoroethane (HFC-134) and1,1,1,2-tetrafluoroethane (HFC-134a)); and hydrofluorpropanes (eg.,1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea)). The relative amount ofthe compound(s) of the present invention, particularly the compounds offormula (I), and the above noted additional propellant components, aswell as any additional components (described hereinafter) which may beincluded in present compositions, can vary widely within the broad scopeof the present invention according to the particular application for thecomposition.

C. Other Components

As is known to those skilled in the art, many modifiers, additives andadjuvants, as well as other propellants, may be included in medicinalcompositions, and all such components are believed to be readilyadaptable for use with the compositions of the present invention. Forexample, medicinal preparations are frequently prepared in the form ofpowdered preparations, sometimes referred to as micronized powders.However, such powders frequently tend to aggregate due to hydrophobic orelectrostatic interactions between the fine particles. Such cohesion maybe at least partially overcome by incorporating into the presentcompositions one or more anti-aggregating agents. One type ofanti-aggregating agent believed to be adaptable for use with the presentcompositions are larger carrier particles, for example, lactose which isthought to inhibit aggregation.

In addition, the present compositions may include one or more otherspecial purpose adjuvants, such as a cosolvent(s) and/or surfactant(s)that enhance the composition. Many embodiments of the presentcompositions may not need co-solvent(s) and/or surfactant(s), dependingupon the interaction between the medically active compound and thepropellant. In certain embodiments a cosolvent may be necessary ordesirable to help dissolve or suspend the medicinally active compound inthe propellant. One important characteristic of the cosolvent which ispreferred or required for many embodiments is that the cosolvent bepharmacologically tolerable. In certain of such embodiments, therefore,the co-solvent(s) are selected from the group consisting ofpharmacologically tolerable hydrocarbons, pharmacologically tolerablealcohols, pharmacologically tolerable esters, pharmacologicallytolerable ethers, water and combinations of any two or more thereof.From among such hydrocarbons, it is preferred in certain embodimentsthat the compositions comprise one or more of propane, butane,isobutene, n-pentane, isopentane, neopentane. From among such alcohols,it is preferred in certain embodiments that the compositions compriseone or more of ethyl alcohol, isopropyl alcohol, propylene glycol, andglycerol. From among such esters, isopropyl mysristate may be mentioned,and from among such ethers, dimethyl ether may be mentioned. Any two ormore of any of these may be used in combination. Of course, it isgenerally preferred in most embodiments that the cosolvent orcombinations of cosolvents be miscible, and even more preferably fullymiscible, with the propellant.

Although the amount of cosolvent used in the present compositions mayvary widely, depending upon numerous factors including the particulartype of medicament and propellant being used, in many embodiments it ispreferred that the composition have a propellant:cosolvent weight ratioof from about 50:50 to about 99:1.

For certain embodiments in which the present medicinal composition is inthe form of a suspension, and particularly an aerosol suspension, thecomposition includes also surfactant(s), in addition to, but preferablyrather than, a cosolvent. While not intending to be bound by or to anyparticular theory of operation, it is believed in such embodiments thatthe surfactant would help to prevent agglomeration of the particles, theadhesion to of the particles to the walls of the container, and providefor lubrication of the dispensing valve. In such embodiments, it isgenerally preferred that the surfactant, when present, is in thecomposition in the amount of not greater than about 5% by weight of thecomposition, although those skilled in the art will appreciate thatgreater amounts may be included depending upon the particulars of eachcomposition and its intended application. While it is contemplated thatcertain surfactants or combinations of surfactants may not be fullysoluble in the present medicinal compositions, or in the propellant inparticular, it is generally preferred to use surfactants which aresoluble in the propellant, and preferably substantially fully soluble inthe propellant under conditions of storage and/or use. Although theamount of surfactant used in the present compositions may vary widely,depending upon numerous factors including the particular type ofmedicament and propellant being used, in many embodiments is preferredthat the compositions have a surfactant:medicament weight ratio of fromabout 1:100 to about 10:1.

Exemplary surfactants which may be used, alone or combination with oneanother in accordance with the present invention include C5-C20 fattyalcohols, C5-C20 fatty acids, C5-C20 fatty acid esters, lecithin,glycerides, propyleneglycol esters, polyoxyethanes, polysorbates,sorbitan esters and carbohydrates. More specific examples of acceptablesurface active agents include oleic acid, sorbitan mono-, di- ortrioleate, and combinations of two or more thereof.

Many embodiments of the present invention, particularly those in whichthe composition is in the form of a suspension, emulsion or dispersion,and particularly an aerosol thereof, preferably include a stabilizingagent. Stabilizing agents for such suspensions, emulsions anddispersions are well known, and it is contemplated that all suchstabilizing agents are adaptable for use in accordance with the presentinvention. Exemplary stabilizing agents include, either alone or incombination, hydrochloric acid, sulphuric acid, nitric acid, phosphoricacid, ascorbic acid, citric acid, benzalkonium chloride, ethylenediamine tetraacetic, and pharmacologically tolerable salts thereof.Although it is contemplated that the stabilizing agents of the presentmentioned it may be included in the compositions in widely varyingamounts, it is generally preferred in many embodiments that thestabilizing agent is present in an amount of from about 40 to about 100ppm by weight of the composition.

As mentioned above, many medicinal compositions provide medicinalcompounds in micro-particulate form, which preferably exhibits arelatively hollow and porous morphology. Such forms are within the scopeof the present invention and are commonly used in MDIs. The use of suchmicro-particulate medicinal compounds in combination with the propellantcomponents in accordance with the present invention is believed toproduce especially stable compositions.

The compositions of the present invention, particularly compositionscomprising or consisting essentially of HFO-1234, are capable ofproviding nonflammable, liquefied gas propellant and aerosols that donot contribute substantially to global warming or ozone depletion. Thepresent compositions therefore provide in certain preferred embodimentssubstantially nonflammable, liquefied gas propellants having very lowGlobal Warming and Ozone Depletion Potentials.

Although the present compositions may be prepared in many forms, incertain embodiments the composition is in the form of an aerosol productfor medical use. The aerosol in preferred embodiments contains at leastone propellant of the present invention along with one or more activemedicinal ingredients, and optionally inert ingredients, stabilizers,surfactant, other propellants and/or solvents. The propellant of thepresent invention preferably at least contributes to, and even morepreferably provides substantially all of the force that expels theproduct in aerosolized form. In accordance with preferred embodiments ofthe present invention, the propellant is a liquefied gas underconditions of storage and use.

II. Devices and Methods

One aspect of the present invention provides a device for the delivery,preferably by inhalation, of a medicament composition of the presentinvention. In certain preferred embodiments, the device comprises acontainer, preferably an aerosol canister, containing a pressurizedmedicament or formulation of the present invention and preferably havinga metered dose dispensing valve operable between non-dispensing anddispensing positions. The present devices preferably also comprise anactuator, which in preferred embodiments comprises a housing adapted toreceive the aerosol container and to define a chamber in fluidcommunication with a patient port for introducing the medicament intothe oral and/or nasal cavity of the patient, preferably in the form of amouthpiece and/or nasal adapter. The actuator also preferably includes anozzle block adapted to receive the valve stem of the dispensing valve,the nozzle block preferably comprising a passage in fluid communicationwith the valve stem and terminating in an orifice for directingmedicament from the valve stem into the chamber.

By way of example but not by way of limitation, in certain embodimentsthe invention device is constructed such that airflow due to patientinhalation is prevented or reduced in the vicinity of the orifice at alltimes or only during dispensing of the medicament from the valve. Eitherof such arrangements has the effect of substantially reducing thevelocity of the emitted spray compared to an inhaler which allows freeflow of air in the vicinity of the nozzle block during dispensing of themedicament.

In certain embodiments, the actuator is constructed such that thedistance from the nozzle to the mouthpiece is from approximately 1 to 15cm, preferably 4 to 6 cm, with a chamber/mouthpiece diameter from 1 to 4cm, 0.5 to 1 cm in the case of a nasal adapter.

In certain preferred but non-limiting embodiments, the actuator possessair inlets which enable the patient to inhale though the patient port,preferably without encountering significant resistance since the patientmay have breathing difficulties when taking the medication, for example,during an asthma attack. However, the air inlets, for example in themouthpiece, preferably do not concentrate the airflow into an area thatis too narrow, as this will give a high velocity of incoming air whichwill deflect the spray onto the wall of the mouthpiece opposite the airinlets. In certain preferred embodiments the air inlets are positioneddownstream of the nozzle, in the region of the turbulent zone and/ordownstream of the turbulent zone. The positioning and direction of theair inlets may also affect the deposition of medicament within thechamber and mouthpiece. In one arrangement air inlets comprise a seriesof holes and optionally may be interdispersed with fluid deflectionstructures on the wall of the chamber, to direct air into the turbulentzone to mix air with the aerosol stream. Further, the mouthpiece may beconstructed of porous material to allow a multiplicity of finely dividedair vents to provide air flow over a larger surface area.

In certain embodiments the actuator possesses air inlets upstream of orin the vicinity of the nozzle but the air inlets are blocked when thevalve is fired to release the aerosol spray. The air inlets are openedafter the spray has been released by which time the velocity of thestream will have been reduced and the turbulent zone formed. Uponinhalation, an airflow is established from the air inlets to themouthpiece which entrains the residual aerosol spray. The actuator mayinclude additional air inlets downstream of the nozzle, as describedabove with respect to the first embodiment. These downstream air inletsdo not need to close during release of the aerosol spray.

In certain embodiments, a porous membrane is present to introduce airinto or downstream of the turbulent zone. One advantage of the use ofsuch a membrane is that the air is introduced more uniformly anddiffusely around the circumference of the spray, thereby acting as abuffer between the turbulent flow and the wall. The effect is to reducedrug deposition in the device. The membrane may optionally be protectedfrom dirt or contact by the user's lips by an additional part of themouthpiece. When present, it is preferred that the porous membranematerial (50) must not significantly impede the patient's ability toinhale through the device. A suitable material is Whatmann No. 4 filterpaper; but other materials may be used, such as those used incylindrical air filters or membrane filters, or such as those formed bysintering polymers. A preferred porous membrane material is in the formof a cylinder made by fusing together small pellets of polypropylene.

For certain medicaments, it is preferred to configure the device so asto reduce contact between the medicament and parts of the patient's bodythat it is not intended to contact. For example, residues of themedicament deposited on internal surfaces of actuators may be fingeredand transferred to other body parts. In such cases, the device may beconfigured to include one or more fluid flow deflectors to allow thespray to pass through, whilst limiting access by the patient to internalsurfaces of the actuator. Of course, the device may be configured forintranasal delivery. This is normally quite undesirable, since themedicaments were designed for delivery to the respiratory system and maynot have an appropriate effect when deposited in the oropharynx andallowed to enter the digestive tract. In an effort to overcome thisproblem, certain embodiments of the present device include the provisionof a holding volume, commonly called a spacer, in which the medicamentis fired. The spacer preferably allows the velocity of the medicament tobe reduced and may also allow some propellant evaporation to occur.Spacers can improve the performance of a metered dose inhaler byreducing oropharyngeal deposition.

One preferred embodiment is disclosed in connection with FIG. 1 Thisdevice comprises an aerosol canister (2) equipped with a metered dosedispensing valve (4) having a valve stem (6). The actuator, generallyshown at (8), comprises a housing (10) which receives the aerosolcontainer (2), a chamber (12) and a mouthpiece (14). A nozzle block (16)receives the valve stem (6) and has a passage (not shown) terminating inan orifice (18) which directs spray from the aerosol valve into thechamber. The housing comprises solid walls (20) in the vicinity of thenozzle block so that there can be no air flow through the device in thevicinity of the orifice. Air inlet passages (22) are positioned towardsthe end of the chamber (12) and are directed towards the mouthpiece(14).

In operation, the aerosol valve is fired and a metered dose of aerosolformulation exits the orifice (18) into the chamber (12). Preferablythere is no air flow in the vicinity of the orifice (18), in which casethe spray is rapidly decelerated and a turbulent zone is formed withinthe chamber (12). As the patient breathes through the mouthpiece (14)air passes through the inlets (22) towards the mouthpiece (14) forming asheath of air around the spray of aerosol formulation. In such preferredembodiments as disclosed in FIG. 1, the inhaler provides substantiallyreduced deposition in the oropharynx of the patient compared with astandard press-and-breathe inhaler, which is also within the scope ofthe present devices.

In other embodiments the mouthpiece may have a bulbed configuration toprovide an increase in cross-sectional area of the mouthpiece downstreamof the turbulent zone followed by a decrease in cross-sectional area atthe extreme downstream end of the mouthpiece. In such embodiments, thebulbed configuration acts in a similar manner to a conventional spacer.

Certain aspects of the present invention thus provide inhalers, andpreferably metered dose inhalers (MDIs) for the treatment of asthma andother chronic obstructive pulmonary diseases and for delivery ofmedicaments to accessible mucous membranes or intranasally. The presentinvention thus includes methods for treating ailments, diseases andsimilar health related problems of an organism (such as a human oranimal) comprising applying a composition of the present inventioncontaining a medicament or other therapeutic component to the organismin need of treatment. In certain preferred embodiments, the step ofapplying the present composition comprises providing an MDI containingthe composition of the present invention (for example, introducing thecomposition into the MDI) and then discharging the present compositionfrom the MDI.

Although the present invention has been described and exemplified abovein connection with certain preferred embodiments, it is not necessarilylimited to these examples and embodiments. The scope of the invention isdefined in accordance with the claims presented hereinbelow and/orpresented hereinafter.

What is claimed is:
 1. A medicinal composition comprising a propellantand at least one medicinally active compound, said propellant comprisingat least 50% by weight of HFO-1234, wherein said HFO-1234 consistsessentially of HFO-1234yf and/or transHFO-1234ze which is a medicinallyacceptable carrier for said medicinally active compound.
 2. (canceled)3. The medicinal composition of claim 1 in the form of a medicinalpreparation for propellant driven application wherein said at least onemedicinally active compound is in the form of a suspension or a solutionwith said propellant.
 4. The medicinal composition of claim 3 wherein atleast one other active substance is in the form of particles suspendedor in solution in the liquid phase.
 5. The medicinal compositionaccording to claim 3 wherein said medicinally active compound comprisesa combination of two or more medicinally active substances solubilizedin said propellant.
 6. The medicinal composition according to claim 1wherein said medically active compound is selected from the groupconsisting of corticosteroids, anti-inflammatories, anti-allergics,long-acting beta agonists, short-acting beta agonists, anticholinergics,proteins and peptides, anti-infectives, pain management, vaccines,hormones, gene therapy vectors, oligonucleotides, immunoglobulins andanti-IgE monoclonal antibodies.
 7. The medicinal composition accordingto claim 1 wherein said medically active compound comprises one or moremedically active ingredients selected from the group consisting ofSalbutamol (albuterol), chiral albuterol, budesonide, epinephrine,formoterol, salmeterol xinafoate, beclomethasone dipropionate,budesonide, cromoglycinic acid, fenoterol, flunisolide, fluticasonepropionate, mometasone furoate, insulin, nedocromil, orciprenaline,oxitropium bromide, repreterol, disodium cromoglycate, pirbuterol,isoprenaline, adrenaline, rimiterol, terbutalin, tiotropium, ipratropiumbromide, epinephrine, omalizumab, the esters, salts, solvates orcombinations thereof.
 8. The medicinal composition of claim 1 furthercomprising at least one surfactant selected from the group consisting ofC5-C20 fatty alcohols, C5-C20 fatty acids, C5-C20 fatty acid esters,lecithin, glycerides, propyleneglycol esters, polyoxyethanes,polysorbates, sorbitan esters and carbohydrates, or combinationsthereof.
 9. The medicinal composition of claim 1 further comprising acosolvent.
 10. The medicinal composition of claim 11 wherein saidcosolvent has a greater polarity than sad propellant.
 11. (canceled) 12.(canceled)
 13. The medicinal composition according to claim 1 whereinthe propellant comprises at least about 50% by weight of HFO-1234. 14.The medicinal composition according to claim 1 wherein the propellantconsists essentially of HFO-1234.
 15. The medicinal compositionaccording to claim 1 wherein said propellant comprises HFO-1234 and oneor more other propellants selected from the group consisting of otherhydrofluoralkenes, hydrofluoroalkanes, fluorocarbons, perfluorocarbons,fluorocarbon/hydrocarbon diblocks, hydrocarbons, alcohols, ethers andcombinations of two or more thereof.
 16. (canceled)
 17. The medicinalcomposition of claim 1 wherein said propellant has a Global WarmingPotential (GWP) of not greater than about
 100. 18. (canceled) 19.(canceled)
 20. An inhaler for medicinal composition comprising acanister containing a medicament formulation, a chamber capable of fluidcommunication with said canister, and a patient port for introducingsaid medicinal composition from said chamber to the oral or nasal cavityof the intended user, said medicinal composition comprising propellantand at least one medicinally active compound, said propellant comprisingat least 50% by weight of HFO-1234, wherein said HFO-1234 consistsessentially of HFO-1234yf and/or transHFO-1234ze.
 21. The inhaler ofclaim 20 wherein said canister is an aerosol canister.
 22. The inhalerof claim 20 wherein said medicinal composition is a pressurizedmedicinal composition.
 23. The inhaler of claim 20 wherein said canistercomprises a metered dose dispensing valve with a valve stem movablebetween non-dispensing and dispensing positions.
 24. (canceled)
 25. Amethod of treating a mammal comprising administering to the mammal amedicinal formulation comprising at least one propellant and at leastone medicinally active compound, said propellant comprising at least 50%by weight of HFO-1234, wherein said HFO-1234 consists essentially ofHFO-1234yf and/or transHFO-1234ze.
 26. (canceled)
 27. The method ofclaim 25 wherein said mammal has a condition capable of treatment byinhalation and said step of administering comprises administering byinhalation and wherein said medicinal composition is an aerosolformulation suitable for aerosol administration.
 28. The methodaccording to claim 27 wherein the condition capable of treatment byinhalation is a respiratory ailment. 29.-31. (canceled)
 32. A method ofmaking an aerosol formulation suitable for delivery to the lung of amammal by inhalation comprising the steps of: (a) providing at least onepropellant, said propellant comprising a medicinally acceptable carrierand comprising at least 50% by weight of HFO-1234, wherein said HFO-1234consists essentially of HFO-1234yf and/or transHFO-1234ze; (b) providingat least one medicinally active compound; and c) introducing saidmedicinally active compound to said propellant such that it is carriedin said propellant.